Influenza and Considerations Regarding Infectious Mimics
- Mar 2nd, 2017
- Erica Simon
Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)
A 57-year-old male with a previous medical history of hypertension and hyperlipidemia presents to the emergency department (ED) with the chief complaint of chills, headache, cough, and generalized malaise. The patient reports the onset of his symptoms 48 hours prior with temperatures peaking at 102.2°F. Review of systems is notable for a sick contact – a granddaughter with “the flu.” The patient denies nausea, vomiting, diarrhea, and abdominal pain. He denies recent travel and reports an inability to obtain an influenza vaccination secondary to a lack of health insurance.
Triage Vital Signs: T103.1°F, HR 126, RR 18, SpO2 95% RA
When approaching this patient, what life threatening conditions that you should be considering? While a diagnosis of influenza is likely high on your list, what clues should you be looking for during the physical examination that might suggest the need for an alternative evaluation and treatment?
Let’s take a minute to review influenza mimics.
Epidemiology of Influenza
In the US, fever, headache, and cough are among the top ten most cited reasons for patients to seek emergency care.1 From 2007-2009, nearly 1 million individuals presenting with the aforementioned symptoms were diagnosed with influenza by an EM physician.2 Complications secondary to influenza result in the annual hospitalization of 220,000 persons,3 representing estimated healthcare costs of $4.6 billion.4 Today influenza demonstrates a mortality rate of 1.4 deaths per 100,000 laboratory-confirmed cases.4
A Review of Influenza
Influenza A, B, and C, named according to their respective surface proteins, are single-stranded RNA viruses capable of human infectivity.5-7 Influenza B and C are responsible for the majority of human infections and are transmitted through aerosolized viral particles.6,7 Influenza A infection (commonly affecting birds, horses, swine, and dogs) may occur through direct contact with an infected animal, exposure to a contaminated environment, or the ingestion of inadequately prepared food stuffs.5
Upon failure of host immunological defenses (IgA secretory antibody and mechanical respiratory mucociliary clearance), influenza viruses invade columnar respiratory epithelium, lymphocytes, polymorphoneuclear leukocytes, and monocytes, resulting in the release of pro-inflammatory cytokines, ultimately affecting a number of organ systems and resulting in variable manifestations of illness.4-8
|Organ System||Organ System Effects of Influenza|
|Respiratory||System most commonly affected: destruction of respiratory epithelium results in edema of the tracheobronchial tree.8,9|
|Neurologic||Influenza virus may directly damage the thalamus, tegmentum, or cerebellum resulting in encephalopathy, seizures, or coma. Viral-associated apoptosis has also been associated with myelitis, Guillain-Barre syndrome, and encephalitis. Reye syndrome may occur in the setting of aspirin administration.8,10|
|Cardiovascular||Pericarditis and myocarditis infrequently occur secondary to influenza A and B infections.8,11|
|Gastrointestinal||Hematogeneous spread of infected lymphocytes may result in emesis and diarrhea.12|
|Hematologic||Leukocytosis is a common cell-mediated immune response to influenza infection.13|
|Musculoskeletal||Myositis and myoglobinuria are frequently observed in the pediatric population and are associated with elevated CK levels.8,14|
Presenting Signs and Symptoms
Malaise, lethargy, and altered mental status may occur at the extremes of age.15 Pediatric patients commonly report nausea, emesis, and abdominal pain, while adults and adolescents detail symptoms including: fever, headache, myalgias, malaise, anorexia, rhinorrhea, pharyngitis, cough, and chest discomfort.4,7,8,15
Although influenza symptoms may be caused by a number of respiratory viruses (RSV, parainfluenza virus, adenovirus, rhinovirus, and coronavirus), in the setting of a local outbreak, current studies identify a provider accuracy of 80-90% in the clinical diagnosis of influenza infection.16-18 Today the Centers for Disease Control and Prevention (CDC) recommends formal diagnostic testing for all patients at high risk of complications secondary to influenza (Table 2).19
|Table 2. Populations at Risk for Influenza Complications19|
|– Children ³ 6 months of age to 4 years (59 months)
– Adults ³ 50 years of age
– Individuals with chronic pulmonary, cardiovascular, renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus)
– Individuals who are immunosuppressed
– Women who are or will be pregnant during influenza season and up to two weeks postpartum
– People ages 6 months – 18 years receiving long-term aspirin therapy and might be at risk for Reye syndrome after influenza infection
– Residents of nursing homes or long-term care facilities
– American Indians/Alaska Natives
– The super obese (body mass index >40)
– Health care personnel
– Caregivers of children <5 years and adults ³ 50 years of age
Numerous mechanisms may be utilized for the identification of influenza infection including: rapid antigen detection tests, direct immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), viral culture, and serology.20,21 Rapid antigen detection tests offer the greatest utility in the emergency setting, as average sample processing time is 15 minutes (reported sensitivity 50-70%, specificity > 90%); however, positive and negative predictive values must be interpreted with respect to the local prevalence of influenza infection and patient presentation.20 False negatives are likely to occur in the midst of the influenza season, when prevalence is high. If a diagnosis is likely to alter clinical decision-making, the CDC recommends confirmation of a negative rapid antigen test with RT-PCR.21
Treatment and Chemoprophylaxis
In the majority of cases, influenza infection is self-resolving and does not require treatment.7 In populations at risk for complications secondary to infection (Table 1), presenting within 48 hours of the onset of symptoms, the CDC recommends treatment with neuraminidase inhibitors according to Table 3 below. Neuraminidase inhibitors prevent viral aggregation and the release of infectious nucleic acids to nearby host cells, therefore limiting infection.21 Double-blinded, placebo-controlled studies of influenza antiviral agents demonstrated an average reduction in febrile influenza illness of 1-1.6 days as compared to placebo when neuraminidase inhibitor therapy was initiated within 48 hours of symptom onset.23-25 This should be weighed against the risk of GI side effects.
Individuals for whom chemoprophylaxis should be considered include unvaccinated family and close contacts of persons with suspected or confirmed cases of influenza at high risk for complications secondary infection.26 In randomized, placebo-controlled trials, oseltamivir and zanamivir were efficacious in the prevention of influenza among persons administered chemoprophylaxis after exposure to a household member of close contact with laboratory confirmed influenza (oseltamivir 68-89%, zanamivir 72-82%).27,28 See Table 3 for chemoprophylaxis recommendations.
Table 3. Influenza Treatment and Chemoprophylaxis Recommendations29
|Antiviral||Delivery Method||Recommendations for Use||Not Recommended for Use||Adverse Effects|
|Oseltamivir (Tamiflu©)||Per Os||Treatment: age ≥ 14 days* Chemoprophylaxis: age ≥ 3 months*||N/A||Nausea, emesis, rare cutaneous reactions, transient neuropsychiatric events.|
|Zanamivir (Relenza©)||Inhalation||Treatment: age ≥ 7 years Chemoprophylaxis: age ≥ 5 years||Persons with respiratory diseases. Contraindicated in patient allergy to milk protein.||Allergic reactions: oropharyngeal or facial edema. Diarrhea, nausea, sinusitis, bronchitis, headache, and ENT infections.|
|Peramivir (Rapivab©)||Intravenous||Age ≥ 18 years||N/A||Diarrhea, rare cutaneous reactions, transient neuropsychiatric events.|
|*FDA-approved indication. The use of oral oseltamivir in the treatment of influenza in infants <14 days, and chemoprophylaxis in infants 3 months to 1 year of age, is recommended by the CDC and American Academy of Pediatrics.|
Current studies indicate that up to 70% of patients presenting with influenza-like illnesses are not infected with the influenza virus.26 Table 4 addresses infectious clinical conditions that commonly present as an influenza-like illness, along with pearls and pitfalls.
Table 4. Infectious Mimics of Influenza
|Patient Presentation||Clinical Condition||Pearl/Pitfall||Treatment|
|Hemodynamic instability or altered mental status||Sepsis30||-Suspected or identified infection in patients meeting two or more of the following Systemic Inflammatory Response Syndrome (SIRS) criteria.||-Early goal directed therapy: fluid resuscitation and antibiotics.|
|Dyspnea and/or chest pain||Pneumonia31||-Patients with multiple medical co-morbidities and the immunosuppressed have an increased likelihood for the development of pulmonary infections.||-Evaluate and address airway and breathing.
-Evaluate for signs/symptoms c/w sepsis or ARDS and treat appropriately.
|Pericarditis32,33||-Viruses are the most common etiology in adults.
-Bacterial pericarditis disproportionately affects children.
|-Viral pericarditis: NSAIDs therapy for 7-14 days following diagnosis.
-Bacterial pericarditis: Broad-spectrum antibiotics, and admit for further evaluation and treatment.
|Infectious Endocarditis (IE)34||-Occurs most commonly in patients > 65 years of age, individuals with CHDs, and IVDAs.
–Staphylococcus and Viridans streptococcus most common pathogens.
-Physical exam important in identifying vascular (septic pulmonary infarct, Janeway lesions, etc.) and immunologic phenomenon (osler nodes, roth spots, etc.)
-Diagnosed according to Duke Criteria
|-Initiate broad-spectrum parenteral antibiotic therapy; patients require admission for evaluation and treatment.|
|Headache, back pain, or myalgias||CNS Infection34,35||-Note: peds patients may present with hypothermia, hypoglycemia, poor feeding, seizures, irritability, bulging fontanelles.
-Pathogens of adult bacterial meningitis: S. pneumoniae, N. meningitides, H. influenza type B, Listeria monocytogenes.
-Pediatrics <2 months of age: Group B Streptococcus.
-Etiologies of viral meningitis: Enteroviruses (50%-75%).35
-Etiologies of encephalitis: herpes family viruses, varicella zoster virus, arboviruses (La Crosse virus, St. Louis virus, West Nile virus, Western Equine virus, Eastern Equine virus).
–HSV (frontal and temporal lobe involvement): taste and smell hallucinations, seizures; SIADH
–West Nile (anterior horn cell involvement): tremors, myoclonus, parkinsonism, flaccid paralysis
–La Crosse (cortical areas involved), most commonly in school-age children; late spring to fall: seizures, disorientation, focal neurologic signs)
–St. Louis (substantia nigra, pons, thalamus, cerebellum involved): tremor, ospoclonus, nystagmus, ataxia, SIADH and urinary symptoms (dysuria, urgency, incontinence)
–Eastern Equine (basal ganglia, thalamus, brainstem involvement), primarily in summer months: seizures
-CT before LP: immunosuppressed, history of CNS disease, new-onset seizure, focal neurologic deficit, papilledema, altered mental status
-Spinal epidural abscess: S. aureus indicated in 60-90% of cases.34
–Adults: often localize to the thoracic spine (50-80% of cases).34
–Pediatrics: abscesses localize to the cervical and lumbar spine.
|-In the setting of bacterial meningitis => antibiotics.
–Dexamethasone for patients > 1 month of age to reduce neurologic sequelae.
-Acyclovir for viral encephalitis.
-Epidural abscess: broad-spectrum antibiotics.
–Consult neurosurg as soon as the diagnosis is suspected.
|Mosquito-borne Illnesses36-40||-Dengue, Yellow Fever and Zika Viruses are arboviruses commonly transmitted by the mosquitos of the Aedes genus.
–Dengue outbreaks reported in Louisiana, Hawaii, Florida, and Texas.
—Presentation may include severe hemorrhagic diathesis, end-organ dysfunction, and hemodynamic collapse. *Dx: PCR and serology.
–Yellow Fever: Endemic to Africa and Central America, rarely occurring in unvaccinated American travelers.
—Presentation ranges from subclinical infection to systemic disease (fever, jaundice, hemorrhage, and renal failure). Dx: serology.
–Zika Virus: flavivirus closely related to dengue. Unlike other arboviruses, Zika virus may also be transmitted through sexual contact and bodily secretions. Local outbreaks have been reported in Florida. A strong association between maternal Zika virus infection and fetal malformations has been identified. Dx: PCR and serology.
–Chikungunya: Prevalent throughout Africa and Asia; first case identified in the U.S. was reported in Florida. Patients report high-grade fevers with disabling arthralgias. Migratory polyarthritis with joint effusions (wrists, fingers, ankles) is common. Vesiculobullous eruptions and ulcers may be present. Dx: PCR
-Malaria: Endemic areas: Haiti, Dominican Republic, Mexico, central and South America, Areas of North and West Africa, India, Asia, and New Guinea.
–History should include discussion of clinical course: P vivax and P ovale cause relapses months after initial infection.
–Dx: thick and thin peripheral smears or PCR.
|-Dengue: supportive care, transfusion if required.
-Yellow Fever: supportive care.
-Zika: Supportive care. Pregnant patients in whom Zika virus infection is a concern should undergo serial ultrasounds (q 3-4 weeks) to identify potential anatomic abnormalities.
-Chikungunya: Most often self-resolving. Rarely, neuro complications including seizures, meningo-encephalitis, and encephalopathy may occur (more common in children).
-Malaria: If suspected, begin treatment with chloroquine or mefloquine.
-If P vivax or P ovale are identified, chloroquine treatment should be followed by primaquine to eradicate the hypnozoite form.
|Acute Retroviral Infection41||-Males who have sex with males represent those at highest risk for HIV contraction.
-Half of all individuals infected with HIV manifest symptoms during the acute phase (fever, sweats, malaise, lethargy, headache, myalgias).
–Positive test results may not occur for up to 12 weeks post exposure (time to generate a detectable humoral response).
|-Consensus guidelines support the strategy of offering antiretroviral therapy to anyone with HIV-related signs or symptoms.|
|Pharyngitis and dysphagia||Epiglottitis42||-Pediatric epiglottitis rare in the U.S. secondary to H. influenza type B vaccination.
-Adult epiglottitis is commonly due to infection by S. pneumoniae, S. pyogenes, or N. meningitides.
-Definitive Dx: laryngoscopy or nasopharyngeal endoscopy.
–Pediatric patients: ideally performed in a controlled setting, immediately prior to securing the airway.
|-Initiate antibiotic therapy with cefotaxime, ceftriaxone, or ampicillin-sulbactam.
–Add vancomycin if bacterial tracheitis cannot be excluded for S. aureus coverage
-Chemoprophylaxis recommended for household contacts of pediatric patients with suspicion of H. influenza type B epiglottitis.
|Deep Space Infection43||-Peritonsillar abscess, Lemierre’s syndrome, retropharyngeal abscess, and Ludwig’s angina commonly present with fever, generalized malaise, sore throat, neck pain, and dysphagia.
–S. aureaus is frequently the pathogen associated with retropharyngeal abscesses; anaerobes are uncommon.
-Lemierre’s syndrome, septic thrombophlebitis of the IJV, is associated with Fusobacterium necrophorum.
-Peritonsillar abscess: evaluate for uvular deviation.
-Cranial neuropathies may indicate contiguous spread of infection to the cavernous sinus.
–Stable patient: consider fiber-optic laryngoscopy.
–Concern for retropharyngeal abscess: AP and lateral neck radiographs. CT if able.
–Concern for peritonsillar abscess: CT neck with IV contrast or ultrasound with endocavitary probe.
–Lemierre’s syndrome or Ludwig’s angina: CT neck with IV contrast.
—CXR in the setting of Lemierre’s may reveal septic emboli.
|-Initiate antibiotic therapy with directed activity against Streptococcus and oral anerobes.
-Retopharyngeal abscess: include S. aureaus coverage.
-Lemierre’s syndrome: metronidazole is first line.
-Most feared complications of deep space infections: airway compromise and mediastinitis.
|Nausea, emesis, diarrhea||GI Infections44|| -Diverticulitis, diverticular abscess, and appendicitis may present with fever, nausea, emesis, and diarrhea.
-History and physical examination guide evaluation and management.
–Systemically ill patient with concern for complicated diverticulitis (requiring surgical evaluation and management) or those who are immunosuppressed, have numerous medical co-morbidities or are elderly: CT with IV and PO contrast: 100% sensitive in identifying pathology.44
|-PO tolerant patient with uncomplicated diverticulitis: discharge home with antibiotic therapy.
-Complicated diverticulitis: fluid resuscitation, parenteral antibiotic therapy, and surgical consultation with consideration for IR if localized abscess.
-Colonoscopy required 3-6 weeks post resolution of diverticulitis/diverticular abscess.
-Appendicitis: fluid resuscitation, IV antibiotics, and surg consult.
|GU Infections45|| -High fever, abdominal pain, and nausea are the hallmarks of tubo-ovarian abscesses (TOAs) and salpingitis.
-The majority of TOAs result from salpingitis, both predominately associated with exposure to sexually transmitted infections (gonorrhea and chlamydia).
–Imaging: Ultrasound or CT with IV contrast are both highly sensitive for the diagnosis of TOA and salpingitis.45
|-Parenteral IV antibiotic therapy is indicated in patients with suspected salpingitis/TOA and should be continued until the patient is asymptomatic, has been afebrile for 24-48 hours, and laboratory studies demonstrate resolution of leukocytosis.45|
The ED Approach
As the presentation of influenza is highly variable, the aforementioned infectious mimics must be considered. In addressing syndromes characterized by fevers, myalgias, headache, cough, or sore throat, abdominal pain, emesis, or diarrhea the emergency physician should:
- Address airway, breathing, and circulation as appropriate and intervene as necessary.
- Make a determination regarding SIRS criteria and initiate early goal directed therapy as appropriate.
- Perform a thorough history utilizing targeted questioning regarding medical comorbidities, immunization status, foreign travel, and sexual practices. Evaluate closely for risk factors for spinal abscess and endocarditis.
- Perform a thorough physical exam to include a neurologic evaluation.
- Focus on meningeal signs, pulmonary findings, rashes, etc.
- Utilize the history and physical examination to make determinations regarding appropriate evaluation, treatment, and disposition.
Back to our case
An appropriate history has elicited medical comorbidities, an immunization deficiency, a sick contact, and the absence of recent travel. A physical examination should be performed, focusing on the findings detailed above. In terms of evaluating for influenza infection, the CDC recommends formal testing for our patient as he is > 50 years of age and possesses medical comorbidities. If we utilize rapid antigen detection, and our patient is presenting during the height of influenza season (Dec-Feb), we must weigh the predictive value of a negative test as false negatives are likely to occur during this time frame. If the rapid antigen test is positive, the patient is PO tolerant, and subsequent examination is otherwise without concerning signs/symptoms, the patient may be prescribed Tamiflu and discharged home.
- The presentation of influenza is variable => adults/adolescents report fevers, myalgias, headache, sore throat, etc. Pediatric patients commonly present with nausea and emesis.
- Healthy adults/adolescents may receive a clinically accurate diagnosis of influenza during a local outbreak.
- Consider the utility of rapid antigen testing during the peak of flu season
- Influenza treatment is appropriate for patients presenting within 48 hours of the onset of symptoms and may reduce the duration of symptomatic illness by up to 1.6 days.25
- Utilize a thorough history and physical exam to evaluate for infectious mimics of influenza.
- Always begin by addressing the ABCs and do not hesitate to initiate early antibiotic therapy.
References / Further Reading
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- Thompson W, Shay D, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292(11):1333-1340.
- The National Institute for Occupational Safety and Health (NIOSH). Seasonal Influenza (Flu) in the Workplace. 2016. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/niosh/topics/flu/activities.html
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- Centers for Disease Control and Prevention. Antiviral agents for the treatment and chemoprophylaxis of influenza: Recommendations of the advisory committee on immunization practices (ACIP). 2011. Available from: http://www.cdc.gov/mmwr/pdf/rr/rr6001.pdf
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